Screening for positive allosteric modulators of cholecystokinin type 1 receptor potentially useful for management of obesity.
Screening for positive allosteric modulators of cholecystokinin type 1 receptor potentially useful for management of obesity.
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DOI：
10.1016/j.slasd.2022.07.001
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发表时间：
2022-10
期刊：
影响因子：
3.1
通讯作者：
Sergienko, Eduard A.
中科院分区：
文献类型：
--
作者：
Dengler, Daniela G.;Sun, Qing;Harikumar, Kaleeckal G.;Miller, Laurence J.;Sergienko, Eduard A.
关键词：
肥胖已成为全球普遍存在的健康负担，尤其是在美国。它与许多健康问题有关，包括心血管疾病、糖尿病和心理健康状况不佳。因此，迫切需要找到安全有效的可持续减肥疗法。胆囊收缩素 (CCK) 被认为是最早通过激活 1 型胆囊收缩素受体 (CCK1R) 来减少暴饮暴食和抑制食欲的胃肠激素之一。一些药物开发活动的重点是寻找 CCK1R 特异性激动剂，这些激动剂在减少膳食量和体重方面显示出良好的功效，但未能获得 FDA 批准，可能是由于与 CCK1R 的有效、持久激活相关的副作用。不具有固有激动剂活性的正变构调节剂 (PAM) 已被提出来克服传统正构激动剂的缺点，并在衰竭的生理系统中恢复 CCK1R 信号传导。然而，寻找此类新型 CCK1R 药物的药物发现活动仍然有限。在这里，我们报告了高通量筛选工作和测试漏斗的建立，这导致了新型 CCK1R 调节剂的鉴定。我们利用 IP-One 积累来开发强大的功能平衡测定，专门用于检测 PAM、激动剂或非特异性激活剂。此外，我们建立了 CCK1R 多重 PAM 测定作为一种新方法来评估功能选择性，能够在同一孔中记录 CCK1R 诱导的 cAMP 积累和 β-arrestin 募集。这种方法的选择和安排使得三种支架的发现成为可能，我们在一系列功能和结合测定中对它们进行了表征和验证。我们发现两个包含四环支架的命中结果显着增强了 CCK1R 的 CCK 信号传导，而不会内在激活过表达系统中的 CCK1R。我们的结果表明，经过深思熟虑的测试漏斗可以识别具有独特药理学特征的小分子，并为开发新型潜在的肥胖治疗方法提供了一个重要的里程碑。
Obesity has become a prevailing health burden globally and particularly in the US. It is associated with many health problems, including cardiovascular disease, diabetes and poorer mental health. Hence, there is a high demand to find safe and effective therapeutics for sustainable weight loss. Cholecystokinin (CCK) has been implicated as one of the first gastrointestinal hormones to reduce overeating and suppress appetite by activating the type 1 cholecystokinin receptor (CCK1R). Several drug development campaigns have focused on finding CCK1R-specific agonists, which showed promising efficacy for reducing meal size and weight, but fell short on FDA approval, likely due to side effects associated with potent, long-lasting activation of CCK1Rs. Positive allosteric modulators (PAMs) without inherent agonist activity have been proposed to overcome the shortcomings of traditional, orthosteric agonists and restore CCK1R signaling in failing physiologic systems. However, drug discovery campaigns searching for such novel acting CCK1R agents remain limited. Here we report a high-throughput screening effort and the establishment of a testing funnel, which led to the identification of novel CCK1R modulators. We utilized IP-One accumulation to develop robust functional equilibrium assays tailored to either detect PAMs, agonists or non-specific activators. In addition, we established the CCK1R multiplex PAM assay as a novel method to evaluate functional selectivity capable of recording CCK1R-induced cAMP accumulation and β-arrestin recruitment in the same well. This selection and arrangement of methods enabled the discovery of three scaffolds, which we characterized and validated in an array of functional and binding assays. We found two hits incorporating a tetracyclic scaffold that significantly enhanced CCK signaling at CCK1Rs without intrinsically activating CCK1Rs in an overexpressing system. Our results demonstrate that a well-thought-out testing funnel can identify small molecules with a distinct pharmacological profile and provides an important milestone for the development of novel potential treatments of obesity.
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DOI：
10.1037/h0034870
发表时间：
1973-01-01
期刊：
JOURNAL OF COMPARATIVE AND PHYSIOLOGICAL PSYCHOLOGY
影响因子：
--
作者：
GIBBS, J;YOUNG, RC;SMITH, GP
通讯作者：
SMITH, GP
影响因子：
4.9
作者：
Christoffersen, Berit O.;Skyggebjerg, Rikke Bjerring;Clausen, Trine Ryberg
通讯作者：
Clausen, Trine Ryberg
影响因子：
2.7
作者：
Desai, Aditya J.;Henke, Brad R.;Miller, Laurence J.
通讯作者：
Miller, Laurence J.
影响因子：
3.6
作者：
Leach, Katie;Davey, Anna E.;Christopoulos, Arthur
通讯作者：
Christopoulos, Arthur
DOI：
10.1177/2472555220945284
发表时间：
2021-01
期刊：
SLAS discovery : advancing life sciences R & D
影响因子：
--
作者：
Dengler DG;Sun Q;Holleran J;Pollari S;Beutel J;Brown BT;Shinoki Iwaya A;Ardecky R;Harikumar KG;Miller LJ;Sergienko EA
通讯作者：
Sergienko EA